Meaningful nomograms based on systemic immune inflammation index predicted survival in metastatic pancreatic cancer patients receiving chemotherapy

Abstract Objective The purpose of the study is to construct meaningful nomogram models according to the independent prognostic factor for metastatic pancreatic cancer receiving chemotherapy. Methods This study is retrospective and consecutively included 143 patients from January 2013 to June 2021. The receiver operating characteristic (ROC) curve with the area under the curve (AUC) is utilized to determine the optimal cut‐off value. The Kaplan–Meier survival analysis, univariate and multivariable Cox regression analysis are exploited to identify the correlation of inflammatory biomarkers and clinicopathological features with survival. R software are run to construct nomograms based on independent risk factors to visualize survival. Nomogram model is examined using calibration curve and decision curve analysis (DCA). Results The best cut‐off values of 966.71, 0.257, and 2.54 for the systemic immunological inflammation index (SII), monocyte‐to‐lymphocyte ratio (MLR), and neutrophil‐to‐lymphocyte ratio (NLR) were obtained by ROC analysis. Cox proportional‐hazards model revealed that baseline SII, history of drinking and metastasis sites were independent prognostic indices for survival. We established prognostic nomograms for primary endpoints of this study. The nomograms' predictive potential and clinical efficacy have been evaluated by calibration curves and DCA. Conclusion We constructed nomograms based on independent prognostic factors, these models have promising applications in clinical practice to assist clinicians in personalizing the management of patients.


| INTRODUCTION
Pancreatic cancer has the reputation of being the king of cancers, data released that China had 134,374 new pancreatic cancer patients and 131,203 pancreatic cancer deaths in 2022, 1 and researches indicated that its prevalence is rising annually, with projections indicating that it will rank as the second most common cause of cancer-related mortality by 2023. 2,3When pancreatic cancer was initially detected, more than half of the patients developed metastases, the 5-year survival rate for metastatic pancreatic cancer is fewer than 5%. 4 Systemic chemotherapy 5 has been proven to be the primary and preferred alternative for metastatic pancreatic cancer patients, the standard first-line regimen is fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX), 6 nab-paclitaxel and gemcitabine (AG), 7 nab-paclitaxel and S-1 (AS), 8 gemcitabine plus S-1 (GS), 9 and common clinical chemotherapy regimen is gemcitabine and oxaliplatin (GEMOX). 10However, in clinical practice, it has been found that patients have the heterogeneous survival prognosis.Therefore, personalized predictive models for metastatic pancreatic cancer patients receiving chemotherapy should be first developed and aim to be used in clinical decision making.Our study collected clinicopathological characteristics, laboratory blood test results and demographic information from patients in our hospital in order to build a prognostic model.Investigating the prognosis survival of patients with metastatic pancreatic cancer treated with first-line chemotherapy is urgently needed, which is why this is being done.With this model, clinicians should be able to better customize treatment plans, which should increase patient survival.
Tumor growth and progression are significantly influenced by tumor microenvironment (TME), 11,12 the proliferation and invasion of tumor cells are facilitated by TME, extracellular matrix, blood vessels and mesenchymal cells are some of the components that give the tumor nourishment and oxygen while also forming the support structures that allow the tumor to grow.Furthermore, the TME's 13,14 signaling molecules and cytokines encourage tumor cells' ability to proliferate, migrate and invade new areas, tumor cells enter the blood or lymphatic system through blood vessels and mesenchymal cells in the TME and form metastases in other tissues and organs, and by interacting with immune cells, tumor cells can suppress their activity and evade the immune system's clearance.Furthermore, immune cell function can be inhibited by immunosuppressive substances and cells in TME, which lowers the immune response to tumors.In TME, cytokines and signaling pathways have the potential to increase tumor cell resistance to specific therapeutic agents and chemotherapeutic drugs. 15The inflammatory response may be one of the markers of tumor growth, which arises from the interaction of immune cells and tumor cells.Peripheral blood counts and TME are correlated, 16 and TME contains a variety of immune cell types, including lymphocytes, monocytes, platelets and so on.Peripheral blood counts can be used to measure the quantity and activity of these immune cells.There are instances where a reduction in the TME's immune cell count causes a corresponding drop in the peripheral blood's immune cell count, 17 white blood cell counts in peripheral blood can rise as a result of an inflammatory reaction in the TME.Because serumbased biomarkers are non-invasive, affordable and easily accessible, as well as having a high correlation with cancer patients' prognosis and individualization, they are becoming a more popular tool for prognostic estimation.Inflammatory statistics including platelet-to-lymphocyte ratio, systemic immunological inflammation index (SII), monocyte-to-lymphocyte ratio (MLR) and neutrophil-tolymphocyte ratio (NLR), can now be used to assess the survival status of patients with pancreatic cancer.For instance, in 2015, 18 it was demonstrated that patients undergoing pancreaticoduodenectomy who had a preoperative NLR ≥2.7 had a much poorer 2-year survival than those whose NLR was <2.7.According to a prospective clinical trials, 19 preoperative SII ≥873, indicates poorer outcomes for patients having pancreatic cancer resection, as opposed to NLR and platelet-to-lymphocyte ratio.Since no prior research has examined the predictive value of SII for predictive potential and clinical efficacy have been evaluated by calibration curves and DCA.

Conclusion:
We constructed nomograms based on independent prognostic factors, these models have promising applications in clinical practice to assist clinicians in personalizing the management of patients.overall survival (OS) and progression-free survival (PFS) in patients with metastatic pancreatic cancer undergoing first-line chemotherapy, the aim of our study is to assess the prognostic importance of SII in these patients.
Tumor prognostic models that are more user-friendly and straightforward to use in clinical settings are constantly being developed thanks to technological advancements.Nomogram 20 which are graphs made up of scales and a sequence of straight lines, are frequently used to quantify and show the extent to which certain factors have an impact on an outcome by charting the lines on the diagram.Typically, a nomogram is made up of scales and a collection of straight lines that combine to create a multidimensional environment.The scale shows the range of values for each line, which reflects an influential factor.The longer the line, generally speaking, the more significant the factor's influence on the outcome; including demographic data and clinicopathological features and inflammatory indicators derived from peripheral blood counts, independent prognostic factors 21 were screened using Cox proportional risk regression models, then, numerous researchers have employed nomogram to visualize study results, facilitate clinical decision-making and survival prediction, using R software reduces complex regression equations into understandable representations so that medical professionals can more readily comprehend and evaluate the predictive model outcomes.In order to visualize the OS and PFS of our patients, we built nomogram models based on SII, history of drinking and metastatic site.

| Patient information
This study is a retrospective clinical trial.By reviewing the case system of Harbin Medical University Cancer Hospital, 143 patients with metastatic pancreatic cancer who were treated with the clinically common twoagent combination chemotherapy regimens of AG, AS, GS and GEMOX at Harbin Medical University Cancer Hospital from January 2013 to June 2021 were consecutively enrolled in this study.After the follow-up period concluded in June 2023, patients who were released from the hospital had routine phone follow-ups.Patients on a regular basis were gathered imaging data and clinical outcomes (survival, death or loss to follow-up).Before receiving chemotherapy, all patients completed an informed consent form after learning about any potential side effects.Inclusion criteria: (1) patients were diagnosed with metastatic pancreatic cancer by pathological diagnosis or imaging examinations; (2) patients received first-line chemotherapy regimens or clinically common chemotherapy regimens.Exclusion criteria: (1) patient received only one cycle of chemotherapy; (2) pMLRatients received blood transfusions before chemotherapy.Demographic and clinicopathological features were collected, including age, sex, primary site, metastasis sites, baseline carcinoembryonic antigen (CEA), baseline carbohydrate antigen 19-9 (CA19-9), the counts of peripheral neutrophils, monocytes, lymphocytes and platelets, body mass index (BMI), history of diabetes, history of smoking and history of drinking.Prior to chemotherapy, complete blood count and tumor markers were obtained within 7 days.In this study, widely used blood biomarkers such as SII, and NLR, were chosen for inclusion.MLR = monocyte count/lymphocyte count; the value of NLR was equal to the ratio of neutrophil count to lymphocyte count; SII = (neutrophil count*platelet count)/ lymphocyte count.The Ethics Committee of the Harbin Medical University Cancer Hospital gave its approval and the study was carried out in compliance with the Declaration of Helsinki.

| Clinical evaluation
The following was how we integrated our chemotherapy regimen in compliance with the standards and our clinical practice: (1) AG; (2) AS; (3) GS; (4) GEMOX.Gemcitabine (1000 mg/m 2 ) d1, d8 intravenously and albumin-bound paclitaxel (125 mg/m 2 ) intravenously, and 3 weeks for 1 cycle of chemotherapy were administered to patients in the AG group; S-1 d1-d14 orally and albumin-bound paclitaxel (125 mg/m 2 )intravenously, and 3 weeks for 1 cycle of chemotherapy were administered to patients in the AS group; gemcitabine (1000 mg/m 2 ) d1, d8 intravenously and S-1 d1-d14 orally, and 3 weeks for 1 cycle of chemotherapy were administered to patients in the GS group; patients in the GEMOX group received gemcitabine (1000 mg/m 2 ) d1, d8 intravenously and oxaliplatin (130 mg/m 2 ) d1 intravenously.The dosage of S-1 was based on body surface area; for body surface areas higher than 1.5 m 2 , higher than 1.25 m 2 and less than 1.5 m 2 ,and less than 1.25m 2 , it was 120 mg/day, 100 mg/day or 80 mg/ day, respectively.Primary endpoints were OS and PSF; the disease control rate (DCR), adverse effects and objective response rate (ORR) were indications of secondary study endpoints.The duration between a patient's first diagnosis and death was defined in the current study as OS, and the time between a patient's initial diagnosis and either tumor progression or death was defined as PFS.Patients with metastatic pancreatic cancer had their treatment responses evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.Utilizing the Common Terminology Criteria for Adverse Events (CTCAE), patients' AEs were evaluated.

| Statistical analysis
Excel was utilized for data management, IBM SPSS Statistics 27 was employed for analyzing the data, and GraphPad Prism 9 and R (version 4.1.1)were utilized for data visualization in the analysis.The measurements were reported as mean ± standard deviation for a normal distribution and as median (interquartile range, IQR) for an abnormal distribution.The expression for count data was a constant (rate) (n [%]).The receiver operating characteristic (ROC) with area under the curve (AUC) was used for the identification of the optimal cut-off value.The Kaplan-Meier survival analysis method with log rank test was utilized to analyze the correlation between patients' survival and the variable.Cox regression analysis was applied to screen for independent prognostic factors of OS and PFS.The "rms" package in R software was run to plot nomograms, calibration curve was a regression model to assess the consistency of novel models.Models' net benefit was evaluated using decision curve analysis (DCA).P < 0.05 represents statistical significance.

| Patient characteristics
We pre-included 897 patients who received a metastatic pancreatic cancer diagnosis at the Harbin Medical University Cancer Hospital between January 2013 and June 2021.We screened 349 patients who received chemotherapy with AS, AG, GS, and GEMOX regimens, 187 patients who received two or more cycles of chemotherapy, 19 patients who received blood transfusions during chemotherapy.Ultimately, our analysis comprised 143 patients with metastatic pancreatic cancer (Figure 1).
Table 1 showed the initial characteristics of each patient, such as age, sex, primary site, metastasis sites, baseline CA19-9, baseline CEA, baseline SII, baseline MLR, baseline NLR, BMI, history of diabetes, history of smoking, history of drinking and systemic chemotherapy regimen.Of the 143 patients, 48 were older than 60 years old, making up 33.5% of the total; 59 patients were female, making up 41.2% of the total; the majority of tumor primary sites were in the pancreatic head; liver metastases accounted for the majority of tumor metastases, making up approximately 70% of the total number of patients; only 81 patients had elevated CEA, and 127 patients had elevated CA19-9.Twelve patients (8.4%) had a BMI of less than 18.5, while 33 patients (23.1%) had a BMI of more than 25.Additionally, 17 patients (11.9%) had a history of diabetes, 28 patients (19.6%) had a history of smoking, and 18 patients (12.6%) had a history of drinking.

| Survival Estimates
We studied the survival of all patients at 2 years after diagnosis, the mOS of patients was 9.7 months.And 7 patients (4.8%) were lost to follow-up and 118 of the 143 patients (82.5%) had died.ROC analysis and AUC determined the optimal SII, NLR and MLR cutoff values of 966.71, 2.54 and 0.257, respectively (p < 0.05) (Figure 2), the sensitivity and specificity were found to be statistically significant (p < 0.05) at 0.373 and 0.96, 0.703 and 0.6, and 0.627 and 0.6, respectively.
The Kaplan-Meier curve and log-rank test were used to assess the prognostic value of age, sex, primary site, metastasis sites, baseline CA19-9, baseline CEA, baseline SII, baseline MLR, baseline NLR, BMI, history of diabetes, history of smoking and history of drinking for predicting OS and PFS.Our findings suggested that higher baseline SII (≥ 966.71), higher baseline MLR (≥0.275) and drinking was correlated with poor OS prognosis (Figure 3A-C); higher baseline SII (≥ 966.71), higher baseline NLR (≥2.54) and liver metastases were associated with worse PFS (Figure 3D-F).
The stratified analysis's findings demonstrated that, in individuals with metastatic pancreatic cancer, the substantial connection between SII and OS was unaffected by age or gender.

| The development of SII-based nomograms for OS and PFS
Univariate Cox regression analysis revealed that drinking, baseline SII, baseline MLR and baseline NLR were connected to OS, baseline SII and history of drinking were found to be independent risk factors for OS (Table 2) by multivariate Cox analysis.A unique nomogram (Figure 5A) was constructed based on these two independent prognostic indicators to visually forecast the 1-and 2-year OS of the included patients.The calibration curves (Figure 5B) demonstrated a good degree of consistency between the actual probability and the anticipated possibilities of the model, while the 1-year DCA curves (Figure 5C) assessed the nomogram's clinical efficacy in this experiment.Meanwhile, baseline SII and metastasis sites were independent prognostic indices for PFS (Table 3) in this analysis.We also developed a nomogram (Figure 5D) of the predicted PFS based on the baseline SII and metastasis sites; similar to this, the calibration curves and DCA were used to assess the nomogram's clinical efficacy and predictive capability.A robust connection was seen between observation and prediction in the 1-and 2-year calibration curves (Figure 5E).The nomogram was therapeutically helpful, according to the 1-year DCA (Figure 5F).

| Efficacy and adverse events of chemotherapy regimens
In this study, the mOS rate for 143 patients was 9.7 months.The mOS rates for the AG, AS, GEMOX and GS regimens were 9.2 months, 11.1 months, 11.2 months and 8.9 months, respectively.The study had 143 patients, of whom 45 (31%) received to the AS regimen, 28 (20%) to the AG regimen, 39 (27%) to the GS regimen, and 31 (22%) to the GEMOX regimen.According to the study's findings, 143 individuals had a mOS of 9.7 months.The median progression-free survival for 143 patients was 8 months,   whereas the mOS for the AS, AG, GS and GEMOX regimens was 11.1 months, 9.2 months, 8.9 months, and 11.2 months, respectively.Table S1 illustrates that the ORR for 143 patients was 6.3%, while the corresponding values for AS, AG, GS and GEMOX were 6.7%, 14.3%, 5.1%, and 0%.The DCR for 143 patients was 49.0%, compared with 40%, 57.1%, 46.2% and 58.1% for AS, AG, GS and GEMOX, respectively (Table S1).
In our retrospective cohort research, the incidence of myelosuppressive adverse reactions was higher than that of other adverse reactions, as Table S2 illustrates.For AS, AG, GS and GEMOX, the corresponding incidence of Grade III-IV adverse events was 11.1%, 7.1%, 2.6% and 6.5% (Table S2).It was evident that the AS regimen had the lowest DCR and the largest prevalence of grade III-IV adverse events.

| DISCUSSION
According to data released by the American Cancer Society, metastatic pancreatic cancer has a low survival rate and ranks third overall in terms of causes of death. 22urrently, the most advanced treatment option for metastatic pancreatic cancer is multi-agent combination chemotherapy.Metastatic pancreatic cancer [23][24][25][26] is known for its extreme heterogeneity and high aggressiveness, which can result in poor individual treatment outcomes and different treatment outcomes for different TMEs.Our clinical work has also shown that chemotherapy affects patients differently even if they have the same stage and metastatic site, thus based on the discovery of independent prognostic markers, clinically significant nomograms can be established to estimate the personalized survival of patients.The FOLFIRINOX and AG regimens have been approved as first-line therapies for metastatic pancreatic cancer by the National Comprehensive Cancer Network in the 10 years following the results of the PRODIGE4/ACCORD 11 and MPACT investigations.Our analysis of patient records from the Harbin Medical University Cancer Hospital, there are relatively few FOLFIRINOX regimens, this is likely because of the high frequency of toxicities and side effects associated with the FOLFIRINOX regimen and the fact that, consequently, we included individuals receiving AS, AG, GS, and GEMOX for metastatic pancreatic cancer.This study's main goal is to gather real-world patient data, organize it, and then use statistical analysis to determine the independent prognostic factors of patients with metastatic pancreatic cancer receiving chemotherapy with regimens that include AS, AG, GS and GEMOX.Additionally, the study aims to find effective biomarkers and build visual nomogram models that will enable timely prediction of the patients' survival probability, which can serve as a guide for clinical staff involved in patient care.
Baseline SII and history of drinking, baseline SII and tumor metastatic site were independent prognostic indicators for OS and PFS, respectively, and had predictive value for patient survival, according to our multivariate Cox proportional risk model analysis.Previous studies by other investigators have shown that peripheral blood routine index [27][28][29][30] is one of the important indicators for assessing TME, tumor inflammatory response, tumor drug resistance, and tumor progression.Peripheral blood cells are closely related to inflammatory response, 31  Abbreviations: AG, nab-paclitaxel and gemcitabine; AS, Nab-paclitaxel and S-1; BMI, body mass index; CA19-9, carbohydrate antigen19-9; CEA, carcinoembryonic antigen; CI, confidence interval; GEMOX, gemcitabine and oxaliplatin, GEMOX; GS, gemcitabine plus S-1; MLR, monocyte-to-lymphocyte ratio; NLR, neutrophil-to-lymphocyte ratio; SII, systemic immune inflammation index.
The bolded numbers (p < 0.05) are super significant findings from this study.
T A B L E 3 (Continued)  tumor development and tumor efficacy response to drugs are inextricably linked to inflammatory response.Inflammatory responses are involved to some extent in tumor formation and progression during tumor development, 17 white blood cell count, neutrophil count, and lymphocyte count in routine peripheral blood indicators can reflect the degree of inflammatory response.Increased neutrophil count 32 may indicate the presence of an inflammatory response in the body, while changes in lymphocyte count [33][34][35] may be related to immune system activity.The process of tumor cell proliferation, invasion, and spread is referred to as tumor progression, increased tumor angiogenesis and invasive ability may be associated with higher neutrophil and platelet counts in regular peripheral blood indicators. 36 Alcohol intake 40 has long been linked to a higher risk of pancreatic cancer and chronic pancreatitis, according to several studies.One possible mechanism 41,42 of alcohol-related carcinogenesis is the body's conversion of alcohol to acetaldehyde, reactive oxygen species, and nitrogen synthesis.It might directly harm cells or cause mechanisms like oxidative stress that result in lipid peroxidation, which lessens the cell's capacity to scavenge free radicals and causes cellular damage and carcinogenesis, or it might affect the metabolism of folate, which modifies DNA methylation and consequently regulates genes that may be involved in the development of cancer.Additionally, drinking alcohol may weaken immune surveillance, which increases the risk of cancer growth and metastasis. 43According to our research, patients with a history of drinking have a worse prognosis, and history of drinking is an independent risk factor for OS.Lu et al. 44 found that Western and heavy drinking may raise the risk of pancreatic cancer, healthy and light-moderate alcohol consumption may lower the risk of pancreatic cancer in a meta-analysis, which was confirmed by another study. 45esearch on alcohol and cancer in clinical, epidemiologic, and experimental contexts is still scarce, despite the significance of alcohol in human carcinogenesis.Controlling alcohol misuse, however, continues to be a key objective of cancer control due to the linear dose-response association between alcohol intake and cancer risk.
The liver is the most typical place where pancreatic cancer metastasizes, but it can also spread to other locations like the peritoneum, lungs, bones and lymph nodes.The majority of patients in this trial had liver metastases; and liver metastases had a statistically significant worse prognosis for PFS than other metastases, according to the Kaplan-Meier curve.Yao et al. 46 looked through the SEER database for 11,287 patients, 601 (5.3%) of whom had lung metastases at the time of PC diagnosis.Patients with lung metastases alone would have a longer OS than those without lung metastases alone, and liver metastasis, chemotherapy were found to be independent prognostic variables for OS and cancer-specific survival, and bone metastasis was an independent predictor of cancer-specific survival.Multiple distant metastases and a poor outcome for chemotherapy recipients were also shown in another investigation, 47 in particular, a total of 2072 cases were found in the SEER database for another study which focused on the prognostic investigation of pancreatic cancer with bone metastases, the analysis conducted revealed that factors such as age, pathology type, chemotherapy administration status, liver metastasis, and lung metastasis were independent predictors of OS, individuals with chemotherapy had a better prognosis, while those with lung and liver metastases had a worse prognosis.In our study, as long as they had liver metastases, the 143 pancreatic cancer patients included in this study were classified as having liver metastases; other metastases from other sites but not liver metastases were classified as belonging to the other metastasis group.In the comprehensive analysis, patients with multisite distant metastases demonstrated a significantly worse prognosis, furthermore, patients with liver metastases of pancreatic cancer may exhibit a more unfavorable prognosis in comparison to other metastases.
In order to illustrate the analysis, our study effectively created nomograms about metastatic pancreatic cancer patients treated with AS, AG, GS, and GEMOX regimens using the R-Project for the independent prognostic factors.Studies demonstrating constructed nomograms, constructed using baseline clinical factors that are readily available prior to chemotherapy, have shown good performance and are very convenient in assisting clinicians in providing individualized management for patients.Zhang et al. 21study included 235 patients screened for pancreatic cancer liver metastases from the SEER database, 167 patients for the training set, 68 patients for the internal validation set as well as retrospectively collected pancreatic cancer patient data.By using Cox regression analysis, it was discovered independent predictors, based on the AUC of ROC analysis, calibration plot and DCA, they concluded that the risk and prognostic model of pancreatic cancer bone metastasis had good performance and the nomogram could accurately predict the risk and prognostic factors of pancreatic cancer bone metastasis.Deng et al. 48enrolled patients with advanced and metastatic pancreatic cancer who received first-line chemotherapy, a validation cohort for this study was subsequently assembled from a prospective study of 236 patients with advanced and metastatic pancreatic cancer receiving first-line chemotherapy, this led to the development of an accurate and well-performing nomogram model based on independent prognostic factors, which will help doctors with the initial survival assessment at the time of diagnosis.Helpful nomograms of research regarding pancreatic cancer patients' survival prognosis are a lot.But our study is the first to model the prediction of OS and PFS using the SII index for nomograms for patients with metastatic pancreatic cancer treated with AS, AG, GS and GEMOX regimens, based on our understanding of realworld studies, and the model performed well in predicting survival.Therefore, it is anticipated that our study will be a useful tool to support clinical decision making.
This study does have certain drawbacks, though.First, because it is a retrospective, single-center cohort study, biases in information and selection may exist.Further validation of our findings through prospective multicenter trials is necessary to lower these bias mistakes and enhance the trustworthiness of the results.To properly apply the measurements to the individualized care of each patient, we also need to record the measures' dynamic changes, because pancreatic cancer is such a highly variable disease, patients' circumstances and reactions to therapy might fluctuate over time.We will therefore be able to comprehend patient illness development and treatment outcomes better if we monitor and record dynamic changes in markers.In conclusion, even with a few drawbacks, this study provides us with a promising new predictive model for nomograms that can be applied to clinical practice.Through further research and validation, we can further improve the accuracy and reliability of the model and use it to assist clinical decision-making and individualized management.

F I G U R E 2
The ROC curve with AUC of SII (A), MLR (B) and NLR (C), p < 0.05 is considered statistically significant.F I G U R E 3 Kaplan-Meier curve and log-rank test for OS based on SII (A), MLR (B) and history of drinking (C), PFS analysis in 143pantients based on SII (D), NLR (E) and metastasis sites (F), p < 0.05 is considered statistically significant.

F I G U R E 4
Correlation of SII with OS in sex (A, B), age (C, D), chemotherapy regimen (E-H) and metastasis sites (I, J) subtypes of metastatic pancreatic cancer receiving chemotherapy, p < 0.05 is considered statistically significant.
The baseline characteristics of patients.
T A B L E 1 T A B L E 1 (Continued) Univariable and multivariable Cox regression of clinical risk factor of OS in all patients.
Univariable and multivariable Cox regression of clinical risk factor of PFS in all patients.
T A B L E 3 and